The alveolar macrophage is the most abundant leukocyte in the lumen of the alveolus and is central to the innate immune system of the lung by promoting phagocytic clearance and by the secretion of cytokines that promote an effective cell mediated immune response to inhaled particulates including microbes and pathogens. The principle cytokines produced during phagocytosis are I-12, TNFα, and IL-18. These macrophage cytokines subsequently induce IFN-γ production by NK cells and Th1 lymphocytes. IFN-γ acts synergistically with these cytokines to promote a Th1 cell mediated immune response and also down-regulate the production of Th2 cytokines, in particular IL-4 and IL-5 which are strong mediators of allergy.
Studies by Shibata et al (1-4), have shown that oral delivery of 1-10 μm phagocytosable chitin particles results in an elevation of Th1 cytokines in mouse spleen cell cultures. The effect was specific to the particulates as no elevation was produced by soluble chitin. It could also be reproduced in 1 μm polystyrene microspheres coated with N-Acetyl-D-Glucosamine, which is the main component of chitin. It was also demonstrated that oral administration of chitin down-regulates serum IgE and lung eosinophilia in a murine model of ragweed allergy (1).
Shibata et al have also developed a mouse model of allergic airway inflammation and orally administered chitin preparations to the mice (Shibata 2000). Ragweed-specific IgE levels were significantly reduced after daily oral administration of chitin to ragweed-sensitised mice, before and during immunisation. Bronchioalveolar lavage (BAL) cells were harvested 14 days after immunisation and a reduction in the levels of eosinophil and lymphocyte levels was observed after chitin treatment. Lung inflammation was determined histologically 14 days after immunisation and the peribronchial, perivascular and total lung inflammation were inhibited in the chitin-treated group.
When chitin was administered prophylactically to mice who were subsequently administered ragweed, IL-4, IL-5 and IL-10 production was significantly reduced and low but significant levels of IFN-γ were detected.
Chitin also has a prophylactic effect when administered to C57BL6 mice, which are higher responders for cell-mediated immunity/Th1 responses, but lower responders for allergic responses compared with BALB/c mice.
When ragweed-sensitised mice were treated simultaneously with ragweed and chitin, the levels of IL IL-5 and IL-10 produced were significantly reduced compared to those stimulated by ragweed alone.
However, while Shibata et al disclose the use of chitin microparticles for the treatment of allergy, the compositions are administered orally as a supplement to activate macrophages and prophylactically strengthen the immune system in the absence of recurrent bacterial infections that are decreasingly common in industrialised countries.
Japanese Patent Application No: 19997-0087986 A (Unitika Limited) discloses the use of deacetylated chitin particles in the form of powders, granules or fibres for delivery to the nasal mucosa. The chitin particles have an effective particle diameter of 20 to 250 microns and are proposed for the treatment of allergic symptoms at an inflammatory site such as pollinosis.
U.S. Pat. No. 5,591,441 (Medical Sciences Research Institute) concerns the use of particulate compositions for providing protection against microorganism infection and biological warfare agents. The compositions are delivered intravenously with the aim of providing a short lived increased in in vivo peroxide levels to kill the microorganisms.
More generally, existing treatments for allergies typically involve the use of steroids to depress the immune system. There are undesirable side effects with steroid therapy. Synthetic drugs, such as steroids are expensive to manufacture, involving a complex process which requires complex quality control and GMP standards to meet requirements of Health and Safety Authorities. In view of these factors, it remains a problem in the art in finding effective treatments for allergy.
Pseudomonas aeruginosa, an opportunistic pathogen, is a leading cause of life threatening infections in immuno-compromised individuals and is a major risk to patients on ventilator support and many disease conditions in which there is a reduction in lung function and a reduced ability to clear infections. Each year, over two million patients die as a result. A report on the incidence of hospital-associated infections places P. aeruginosa among the three most frequently reported pathogens (5). P. aeruginosa is also a common cause of chronic and life threatening pulmonary infection in cystic fibrosis patients. Recent reports list P. aeruginosa among the most serious antibiotic-resistant bacteria and one for which effective vaccines are needed (6). Streptococcus pneumoniae is a ubiquitous pathogen and responsible for a high proportion of cases of pneumonia (both lobar and bronchopneumonia) and one of the leading causes of illness and death among young children, the elderly and those with an impaired immune system as the result of diseases, such as AIDS, or immunosuppressive therapy, such as for bone marrow transplantation. The invasive form of Streptococcal infection, in which the bacteria disseminate into the blood and other organs leads to very serious complications. Each year in the United States, pneumococcal disease is estimated to cause 3000 cases of meningitis, 50,000 cases of bacteraemia, 125,000 hospitalisations and 6,000,000 cases of Otitis media.
There is a growing concern about the emergence of antibiotic resistant strains of S. pneumoniae and there is a considerable amount of research into new treatments and vaccines.